Poor-prognosis estrogen receptor-positive breast cancer identified by histopathologic subclassification.

PURPOSE: Identification of biologically and clinically distinct breast cancer subtypes could improve prognostic assessment of primary tumors. The characteristics of "molecular" breast cancer subtypes suggest that routinely assessed histopathologic features in combination with limited biomarkers may provide an informative classification for routine use. EXPERIMENTAL DESIGN: Hierarchical cluster analysis based on components of histopathologic grade (tubule formation, nuclear pleomorphism, and mitotic score), expression of ER, cytokeratin 5/6, and HER2 amplification identified four breast cancer subgroups in a cohort of 270 cases. Cluster subgroup membership was compared with observed and Adjuvant! Online predicted 10-year survival. Survival characteristics were confirmed in an independent cohort of 300 cases assigned to cluster subgroups using a decision tree model. RESULTS: Four distinct breast cancer cluster subgroups (A-D) were identified that were analogous to molecular tumor types and showed a significant association with survival in both the original and validation cohorts (P < 0.001). There was a striking difference between survival for patients in cluster subgroups A and B with ER(+) breast cancer (P < 0.001). Outcome for all tumor types was well estimated by Adjuvant! Online, with the exception of cluster B ER(+) cancers where Adjuvant! Online was too optimistic. CONCLUSIONS: Breast cancer subclassification based on readily accessible pathologic features could improve prognostic assessment of ER(+) breast cancer.

Uncovering the potential risk of serotonin toxicity in Australian veterans using pharmaceutical claims data.

AIMS: We examined potential risk of serotonin toxicity in Australian veterans by quantifying the concomitant use of serotonergic medicine combinations from claims data collected by the Department of Veterans' Affairs (DVA). METHODS: This was a retrospective cohort study of 273 228 Australian veterans, war widows, widowers and dependents aged >or=55 years and holding full treatment entitlement for the period July 2000 to June 2004 or until death. The main outcome measure was potential concomitant use, estimated as the number of cohort members with an overlap in days of supply for serotonergic medicine combinations over the 4 year period for all medicine combinations and potentially life threatening combinations. RESULTS: From July 2000 to June 2004, 115 969 (42%) cohort members were dispensed at least one serotonergic medicine. 20 658 (8%) had at least one episode of potential concomitant use. We identified 1811 (0.7%) cohort members with at least one overlapping period of potentially life-threatening serotonergic medicine combinations, 937 of whom had the combinations dispensed within the recommended washout period. Three hundred and seventeen of these individuals were dispensed potentially life-threatening medicine combinations on the same day. The most common combinations were moclobemide with a selective serotonin reuptake inhibitor or tramadol. CONCLUSIONS: The individuals potentially at risk of mild to moderate serotonin toxicity were considerable and potentially life threatening combinations were not infrequent. While we were unable to determine how many individuals experienced serotonin toxicity this study indicates, for the first time, the potential size of the problem in a subgroup of elderly Australians. Clinicians and patients need to be vigilant regarding inadvertent concomitant use, especially that of moclobemide with a selective serotonin reuptake inhibitor or tramadol.

Trastuzumab and metastatic breast cancer: trastuzumab use in Australia--monitoring the effect of an expensive medicine access program.

PURPOSE: Data from clinical trials are used for drug registration; however, many cancer medicines are ultimately used off-label. This study examines the extent to which the clinical practice use of trastuzumab for the treatment of metastatic breast cancer differs from its use under trial conditions. METHODS: This study involved all women (N = 1,469) with metastatic breast cancer who received trastuzumab in Australia between December 2001 and March 2005. Given that Australia operates a universal health care system, administrative databases could be examined to determine the duration of therapy, rate of off-label use, compliance with cardiac monitoring, and the extent of drug wastage (volume and cost). RESULTS: A total of 433 enrollees (29.5%) received trastuzumab as monotherapy and 1,036 enrollees (70.5%) received the drug in combination with chemotherapy. A total of 321 women (22%) received off-label trastuzumab. The median duration of trastuzumab therapy was longer than that on trial: 5.6 v 3.1 months for enrollees receiving monotherapy and 12.5 v 6.9 months for concomitant chemotherapy. Only 47 (3%) of enrollees received cardiac monitoring before and during trastuzumab therapy. We estimated 24% of trastuzumab dispensed was discarded, at a cost of $21.1 million Australian. Alternative administration schedules and the addition of another vial size potentially reduce wastage to 6% of volume dispensed. CONCLUSION: Debates about the use of expensive cancer medicines should consider postmarketing assessments as well as trial experience. The longer duration of trastuzumab use in clinical practice and the high rates of off-label use provide incentive for new clinical trials. Strategies to improve cardiac monitoring and to minimize drug wastage are issues that require immediate attention.

Reattendance at hospital for asthma in two Australian states, 2000-2003.

OBJECTIVE AND BACKGROUND: Reattendance rates at hospitals and emergency departments (ED) can provide a valuable marker of the quality and effectiveness of clinical care. Linked hospital and ED data from New South Wales and Victoria, Australia, were used to examine reattendances for asthma. METHODS: Hospital and ED data were linked to identify individuals who reattended hospital or ED for asthma within 28 days of an initial attendance. The sociodemographic characteristics that predicted reattendance were examined using logistic regression. RESULTS: There were 139,043 attendances for asthma between July 2000 and June 2003 attributed to 95,042 people. Overall, 7.1% of people reattended for asthma within 28 days. There was a significantly higher risk of reattendance among females (odds ratio (OR) 1.09, 95% confidence interval (CI) 1.03-1.14), people who lived in areas of greater socioeconomic disadvantage (OR 1.20, 95% CI 1.12-1.29) and Indigenous people (OR 1.15, 95% CI 1.00-1.32). Reattendance rates differed among age groups (P < 0.001), with the lowest rate being in 5- to 14-year-olds. CONCLUSION: The availability of linked hospital and ED data has provided a rare opportunity to investigate predictors of reattendance for asthma. Surveillance of trends in reattendances for asthma can be used to monitor the effectiveness of interventions to improve asthma control across the continuum of care, particularly in higher-risk groups such as Indigenous people, young children and those with greater socioeconomic disadvantage.

Hospital readmissions for asthma: a feasibility study comparing strategies for linking hospital morbidity data.

OBJECTIVE: To investigate whether the variables in the National Hospital Morbidity Database (NHMD) provide sufficient information to validly link hospital admission records for the same person so that persons admitted and re-admissions for a specified disease can be enumerated. METHODS: Records of hospital admissions where asthma was the principal diagnosis were extracted from the New South Wales Inpatient Statistics Collection for the period July 2000 to June 2003 and linked using several strategies. The optimal' strategy applied probabilistic record linkage, using many demographic and administrative variables. A range of restricted strategies, using only those variables that were available with the NHMD (sex, date of birth, and either postcode or statistical local area of residence) and linking them deterministically, were evaluated and their validity for quantifying readmission for asthma within 28 days was assessed relative to the optimal strategy. RESULTS: The optimal and restricted linkage strategies obtained similar estimates of readmissions. Approximately 95% of readmissions within 28 days identified using the optimal strategy were also identified using the restricted strategies. CONCLUSIONS: Linking hospital records where asthma was the principal diagnosis using only those variables available in the NHMD enabled reliable identification of hospital readmissions tor asthma. IMPLICATIONS: This methodology may have useful applications for monitoring the rate of readmissions for asthma and other chronic diseases nationally.

Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis.

BACKGROUND: The duration and cost of cancer clinical trials could be reduced if a surrogate endpoint were used in place of survival. We did a meta-analysis to assess the extent to which two surrogates, tumour response and time to progression, are predictive of mortality in metastatic colorectal cancer and non-small-cell lung cancer. METHODS: Summary data (median time to progression, proportion of patients responding to treatment, and median overall survival) from randomised trials of first-line treatment in colorectal cancer (146 trials) and lung cancer (191 trials) were identified. Data were extracted and analysed by linear regression. We used prediction bands for trials with 250, 500, and 750 patients to identify the surrogate threshold effect that would predict a significant difference in survival. FINDINGS: Response to treatment and time to progression correlated with improvement in survival for both lung cancer (p<0.0001 and p=0.0003, respectively) and colorectal cancer (p<0.0001 for both). To predict a significant survival gain in colorectal cancer trials, an improvement of 20% in the number of patients responding to treatment was required in trials with 750 patients, increasing to 26% in trials with 500 patients and 38% in trials with 250 patients. In lung cancer trials, the same prediction required differences in response of 18% for 750 patients, 21% for 500 patients, and 30% for 250 patients. For time to progression for both cancer types, the incremental gain needed to predict a survival improvement was a median of 1.8 months for trials with 750 patients, 2.2 months for 500 patients, and 3.3 months for 250 patients. INTERPRETATION: Irrespective of trial size, large differences in tumour response rate are needed to predict a significant survival benefit. If surrogates are chosen as the primary endpoint in a clinical trial, time to progression is the preferred measure because more modest and achievable differences are needed for a significant survival benefit. Trials in metastatic lung cancer and colorectal cancer should measure survival as their primary outcome unless the surrogate outcome difference is anticipated to exceed the threshold effect size.

Sexual behaviour and human herpesvirus 8 infection in homosexual men in Australia.

BACKGROUND: Human herpesvirus 8 (HHV-8) is a common sexually transmitted agent among homosexual men, but there are few Australian data. We aimed to describe the prevalence and risk factors for seropositivity to HHV-8 in Australian homosexual men. METHODS: We conducted a prospective cohort study of 179 homosexual men in Sydney Australia in 1992-1998. Detailed data on sexual behaviour was collected annually, and HHV-8 status was determined at the end of the study by an algorithm based on results of an immunofluorescence assay and an enzyme-linked immunoassay to the K8.1 protein of HHV-8. HHV-8 DNA was detected in buffy coats using a nested qualitative PCR. RESULTS: Data on sexual behaviour in at least three interviews and HHV-8 status were available in 174 (97%) of 179 men who agreed to participate. Of these, 31 (18%) were HHV-8 seropositive, and HHV-8 DNA was detected in 5 (16%) of these. The prevalence of HHV-8 infection was much higher in HIV positive (52%) than HIV negative (11%) men (OR 8.60, 95% CI 3.55-20.86). HHV-8 infection was related to more frequent reporting of unprotected receptive anal sex (OR for most frequent versus least frequent category 3.03, 95% CI 1.01-9.03, P trend 0.02), insertive oro-anal sex (OR for most frequent v. least frequent category 3.02, 95% CI 1.15-7.93, P trend 0.02) and receptive oro-anal sex (OR for most frequent v. least frequent category 3.09, 95% CI 1.11-8.60, P trend 0.05) with casual partners. CONCLUSIONS: These data are consistent with sexual transmission of HHV-8, but the precise mode of HHV-8 transmission remains unclear. Studies to elucidate the precise mode of sexual transmission of HHV-8 need to focus on potential salivary transmission, and should collect data on the HHV-8 infection and excretion status of the sexual partner.

Demographic and socio-economic factors associated with dental health among older people in NSW.

OBJECTIVE: To investigate the association between oral health status and social, economic and demographic factors in community-dwelling older people in New South Wales (NSW). METHODS: Binary and multinomial logistic regression analyses were used to examine the associations between measures of oral health status (edentulous/dentate, and the frequency of toothache or mouth or denture problems in the previous 12 months) and demographic and socio-economic factors using data from the NSW Older People's Health Survey 1999. RESULTS: After adjusting for other factors, being edentulous was associated with being older, having no private dental insurance, being female, leaving school at less than 15 years of age, not being financially comfortable, not being a homeowner, living in a rural area, and being unable to travel alone. Among both dentate and edentulous people, increasing age and being able to travel independently were associated with decreased reporting of toothache, mouth or denture problems; while not being financially comfortable was associated with increased reporting of toothache or mouth or denture problems. The frequency of mouth or denture problems was not found to be independently associated with having private dental insurance nor with holding a health concession card. CONCLUSIONS: Among older people in NSW, oral health is associated with a range of demographic and socio-economic factors. The results suggest that better oral health among older people is associated with a capacity to pay out-of-pocket dental expenses rather than with private dental insurance or having access to public-funded dental care.

Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study.

OBJECTIVE: To determine if long-term improvement in HIV lipoatrophy can be attained by substitution of thymidine analogues zidovudine (ZDV) or stavudine (d4T) with abacavir (ABC). DESIGN: Long-term follow-up (104 weeks) of a randomized, open-label study. SETTING: Seventeen ambulatory HIV clinics in Australia and London. SUBJECTS: Patients with HIV lipodystrophy were randomized to switch from a thymidine analogue to ABC, while continuing all other antiretroviral therapy (ABC arm) (n = 42) or continue current therapy (ZDV/d4T arm) (n = 43). INTERVENTION: At week 24, all control patients could switch to ABC. Of the original 111 patients randomized, 85 had long-term follow-up data, with 77 having imaging data available at 104 weeks. MAIN OUTCOME MEASURE: The primary endpoint was time-weighted change in limb fat mass, measured by dual-energy X-ray absorptiometry (DEXA). RESULTS: At week 104, the mean increase in limb fat for the ABC and ZDV/d4T group was 1.26 +/- 2.02 kg and 0.49 +/- 1.38 kg, respectively. The time-weighted change for limb fat was significantly different between the two arms (0.43 kg; P = 0.008). On-treatment analysis demonstrated a trend for increased limb fat in patients in the ABC arm. Visceral fat accumulation, buffalo hump, self-assessed lipodystrophy or the lipodystrophy case definition score (LCDS) did not improve. CONCLUSIONS: In patients with moderate-to-severe lipodystrophy, significant improvements in subcutaneous fat continued over 104 weeks after switching from a thymidine analogue to ABC. Nevertheless, the lipodystrophy syndrome was still evident, indicating additional strategies need evaluating.

A comparison of practice outcomes of graduates from traditional and non-traditional medical schools in Australia.

AIM: The primary aim of the study was to compare the practice outcomes of doctors who graduated from a non-traditional, problem-based medical school (University of Newcastle) with those of graduates from a traditional programme (University of Sydney), matched randomly on the background characteristics of graduation year, age, gender, and rural primary and secondary school education. Our secondary aim was to differentiate admission from curricular influences by comparing the outcomes of Newcastle and Sydney graduates who entered medical school under similar admission criteria ('traditional academic' entry). DESIGN: Nested case-control analysis in a retrospective cohort study. METHODS: A validated mail-out survey was distributed to all Newcastle and Sydney graduates registered to practise in the state of New South Wales, Australia. OUTCOME MEASURES: Current main occupation (clinician or other), clinical career choice (family medicine and psychiatry or other specialties), practice location (urban or rural) and employment sector (public or private). RESULTS: A total of 513 Newcastle respondents (68% of the original, eligible Newcastle sample) were each matched randomly with a Sydney respondent according to the four background characteristics. Medical school background was not related to main occupation; over 90% of all graduates were employed in clinician positions. A greater proportion of Newcastle than Sydney graduates were either training or qualified in family medicine or psychiatry rather than in other specialties. The school of graduation was not related to practice environment; fewer than 20% of all graduates were working in rural locations and around 25% were employed in the public sector. There were no differences in outcome between Newcastle and Sydney graduates who had entered medical school under similar academic criteria. CONCLUSION: Our study suggests that initial selection procedures of medical school candidates with particular background characteristics and attributes may influence practice outcomes. Further research is required to confirm these findings.